This invention relates to a method for the selective inhibition of neoplastic cells, for example, for the treatment or prevention of precancerous lesions or other neoplasias in mammals.
Each year in the United States alone, untold numbers of people develop precancerous lesions, which is a form of neoplasia, as discussed below. Such lesions exhibit a strong tendency to develop into malignant tumors, or cancer. Such lesions include lesions of the breast (that can develop into breast cancer), lesions of the skin (that can develop into malignant melanoma or basal cell carcinoma), colonic adenomatous polyps (that can develop into colon cancer), and other such neoplasms. Compounds that prevent or induce the remission of existing precancerous or cancerous lesions or carcinomas would greatly reduce illness and death from cancer.
For example, approximately 60,000 people die from colon cancer, and over 150,000 new cases of colon cancer are diagnosed each year. For the American population as a whole, individuals have a six percent lifetime risk of developing colon cancer, making it the second most prevalent form of cancer in the country. Colon cancer is also prevalent in Western Europe. It is believed that increased dietary fat consumption is increasing the risk of colon cancer in Japan.
In addition, the incidence of colon cancer reportedly increases with age, particularly after the age of 40. Since the mean ages of populations in America and Western Europe are increasing, the prevalence of colorectal cancer should increase in the future.
To date, little progress has been made in the prevention and treatment of colorectal cancer, as reflected by the lack of change in the five-year survival rate over the last few decades. The only cure for this cancer is surgery at an extremely early stage. Unfortunately, most of these cancers are discovered too late for surgical cure. In many cases, the patient does not experience symptoms until the cancer has progressed to a malignant stage.
In view of these grim statistics, efforts in recent years have concentrated on colon cancer prevention. Colon cancer usually arises from pre-existing benign neoplastic growths known as polyps. Prevention efforts have emphasized the identification and removal of colonic polyps. Polyps are identified by x-ray and/or colonoscopy, and usually removed by devices associated with the colonoscope. The increased use of colon x-rays and clonoscopies in recent years has detected clinically significant precancerous polyps in four to six times the number of individuals per year that acquire colon cancer. During the past five years alone, an estimated 3.5 to 5.5 million people in the United States have been diagnosed with adenomatous colonic polyps, and it is estimated that many more people have or are susceptible to developing this condition, but are as yet undiagnosed. In fact, there are estimates that 10-12 percent of people over the age of 40 will form clinically significant adenomatous polyps.
Removal of polyps has been accomplished either with surgery or fiber-optic endoscopic polypectomyxe2x80x94procedures that are uncomfortable, costly (the cost of a single polypectomy ranges between $1,000 and $1,500 for endoscopic treatment and more for surgery), and involve a small but significant risk of colon perforation. Overall, about $2.5 billion is spent annually in the United States in colon cancer treatment and prevention.
In the breast, breast cancer is often treated surgically, often by radical mastectomy with its painful aftermath. Such surgery is costly, too.
As indicated above, each lesion carries with it a chance that it will develop into a cancer. The likelihood of cancer is diminished if a precancerous lesion is removed. However, many of these patients demonstrate a propensity for developing additional lesions in the future. They must, therefore, be monitored periodically for the rest of their lives for reoccurrence.
In most cases (i.e. the cases of sporadic lesion formation, e.g. so-called common sporadic polyps), lesion removal will be effective to reduce the risk of cancer. In a small percentage of cases (i.e. cases where numerous lesions form, e.g. the so-called polyposis syndromes), removal of all or part of the effected area (e.g. the colon) is indicated. For example, the difference between common sporadic polyps and polyposis syndromes is dramatic. Common sporadic polyp cases are characterized by relatively few polyps which can usually be removed leaving the colon intact. By contrast, polyposis syndrome cases can be characterized by many (e.g. hundreds or more) of polypsxe2x80x94literally covering the colon in some casesxe2x80x94making safe removal of the polyps impossible short of surgical removal of the colon.
Because each lesion carries with it a palpable risk of cancerous development, patients who form many lesions (e.g. polyposis syndrome patients) invariably develop cancer if left untreated. Surgical removal of the colon is the conventional treatment in polyposis patients. Many polyposis patients have undergone a severe change in lifestyle as a result of the disfiguring surgery. Patients have strict dietary restrictions, and many must wear ostomy appliances to collect their intestinal wastes.
The search for drugs useful for treating and preventing cancer is intensive. Indeed, much of the focus of cancer research today is on the prevention of cancer because chemotherapy for cancer itself is often not effective and has severe side effects. Cancer chemoprevention is important for recovered cancer patients who retain a risk of cancer reoccurrence. Also, cancer prevention is important for people who have not yet had cancer, but have hereditary factors that place them at risk of developing cancer. With the development of new genetic screening technologies, it is easier to identify those patients with high-risk genetic factors, such as the potential for polyposis syndrome, who would greatly benefit from chemopreventative drugs. Therefore, finding such anti-cancer drugs that can be used for prolonged preventive use is of vital interest.
Known chemopreventative and chemotherapeutic drugs are believed to kill cancer cells by inducing apoptosis, sometimes referred to as xe2x80x9cprogrammed cell death.xe2x80x9d Apoptosis naturally occurs in virtually all tissues of the body, and especially in self-renewing tissues such as bone marrow, immune cells, gut, liver and skin. Apoptosis plays a critical role in tissue homeostasis, that is, it ensures that the number of new cells produced are correspondingly offset by an equal number of cells that die. For example, the cells in the intestinal lining divide so rapidly that the body must eliminate cells after only three days in order to prevent the overgrowth of the intestinal lining.
Recently, scientists have realized that abnormalities of apoptosis can lead to the formation of precancerous lesions and carcinomas. Also, recent research indicates that defects in apoptosis play a major role in other diseases in addition to cancer. Consequently, compounds that modulate apoptosis could be used to prevent or control cancer, as well as used in the treatment of other diseases.
Unfortunately, even though known chemotherapeutic drugs may exhibit such desirable apoptosis effects, most chemotherapeutic drugs have serious side effects that prohibit their long-term use, or use in otherwise healthy individuals with precancerous lesions. These side effects, which are a result of the high levels of cytotoxicity of the drugs, include hair loss, weight loss, vomiting, immune suppression and other toxicities. Therefore, there is a need to identify new drug candidates for therapy that do not have such serious side effects in humans.
In recent years, several non-steroidal anti-inflammatory drugs (xe2x80x9cNSAIDsxe2x80x9d), originally developed to treat arthritis, have shown effectiveness in inhibiting and eliminating colonic polyps. Polyps virtually disappear when the patients take the drug, particularly when the NSAID sulindac is administered. However, the prophylactic use of currently available NSAIDs, even in polyposis syndrome patients, is marked by severe side reactions that include gastrointestinal irritations, perforations, ulcerations and kidney toxicity. Once NSAID treatment is terminated due to such complications, the polyps return, particularly in polyposis syndrome patients.
Sulindac has been particularly well received among the NSAlDs for polyp treatment. Sulindac is a sulfoxide compound that itself is believed to be inactive as an anti-arthritic agent. The sulfoxide is reportedly converted by liver enzymes to the corresponding sulfide, which is acknowledged to be the active moiety as a prostaglandin synthesis inhibitor. The sulfide, however, is associated with the side effects of conventional NSAIDs. The sulfoxide is also known to be metabolized to a sulfone compound that has been found to be inactive as an inhibitor of prostaglandin synthesis but active as an inhibitor of precancerous lesions.
This invention includes a method of inhibiting neoplastic cells by exposing those cells to a pharmacologically effective amount of those compounds described below. Such compounds are effective in modulating apoptosis and eliminating and inhibiting the growth of neoplasias such as precancerous lesions, but are not characterized by the severe side reactions of conventional NSAIDs or other chemotherapeutics.
The compounds of that are useful in the methods of this invention include those of Formula I: 
wherein
R1 is selected from the group consisting of hydrogen, halogen, nitro, carboxy, protected carboxy, acyl, cyano, hydroxyimino(lower)alkyl, lower alkenyl optionally substituted with oxo, or lower alkyl optionally substituted with protected carboxy, carboxy or hydroxy;
R2 is selected from the group consisting of hydrogen, halogen, lower alkenyl, acyl, or lower alkyl optionally substituted with protected carboxy, carboxy, lower alkoxy, or hydroxy, or R1 and R2, together with the carbon atoms to which they are attached form a 4- to 7-membered carbocyclic ring optionally substituted with Oxo;
R3 is selected from the group consisting of lower alkenyl or lower alkyl, both of which are optionally substituted with one or more substituent(s) selected from the group consisting of (1) oxo, (2)aryl optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, lower alkoxy, lower aklylenedioxy, cyano, nitro, carboxy, protected carboxy, acyl, and amino optionally substituted with acyl or protected carboxy, and (3) a heterocyclic group optionally substituted with halogen; and
R4 is selected from the group consisting of carboxy, protected carboxy, acyl, cyano, halogen, a heterocyclic group, amino optionally substituted with acyl or protected carboxy, or lower alkyl optionally substituted with protected carboxy, carboxy, or acyl;
or its pharmaceutically acceptable salts
As indicated above, this invention relates to a method for inhibiting neoplasia, particularly cancerous and precancerous lesions by exposing the affected cells to a compound of Formula I above.
Preferably, such compounds are administered without therapeutic amounts of an NSAID.
The present invention is also a method of treating mammals with precancerous lesions by administering a pharmacologically effective amount of an enterically coated pharmaceutical composition that includes compounds of this invention.
Also, the present invention is a method of inhibiting the growth of neoplastic cells by exposing the cells to an effective amount of compounds of Formula I, wherein R1 through R3 are defined as above.
In still another form, the invention is a method of inducing apoptosis in human cells by exposing those cells to an effective amount of compounds of Formula I to those cells sensitive to such a compound.
As used herein, the term xe2x80x9cprecancerous lesionxe2x80x9d includes syndromes represented by abnormal neoplastic, including dysplastic, changes of tissue.
Examples include adenomatous growths in colonic, breast or lung tissues, or conditions such as dysplastic nevus syndrome, a precursor to malignant melanoma of the skin. Examples also include, in addition to dysplastic nevus syndromes, polyposis syndromes, colonic polyps, precancerous lesions of the cervix (i.e., cervical dysplasia), prostatic dysplasia, bronchial dysplasia, breast, bladder and/or skin and related conditions (e.g., actinic keratosis), whether the lesions are clinically identifiable or not.
As used herein, the term xe2x80x9ccarcinomasxe2x80x9d refers to lesions that are cancerous. Examples include malignant melanomas, breast cancer, and colon cancer.
As used herein, the term xe2x80x9cneoplasmxe2x80x9d refers to both precancerous and cancerous lesions.
It will also be appreciated that a compound of Formula I or a physiologically acceptable salt or solvate thereof can be administered as the raw compound, or as a pharmaceutical composition containing either entity.
Compounds useful in the methods of this invention are preferably formulated into compositions together with pharmaceutically acceptable carriers for oral administration in solid or liquid form, or for rectal administration, although carriers for oral administration are most preferred.
Pharmaceutically acceptable carriers for oral administration include capsules, tablets, pills, powders, troches and granules. In such solid dosage forms, the carrier can comprise at least one inert diluent such as sucrose, lactose or starch. Such carriers can also comprise, as is normal practice, additional substances other than diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, troches and pills, the carriers may also comprise buffering agents. Carriers such as tablets, pills and granules can be prepared with enteric coatings on the surfaces of the tablets, pills or granules. Alternatively, the enterically coated compound can be pressed into a tablet, pill, or granule, and the tablet, pill or granules for administration to the patient. Preferred enteric coatings include those that dissolve or disintegrate at colonic pH such as shellac or Eudraget S.
Pharmaceutically acceptable carriers include liquid dosage forms for oral administration, e.g. pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
Pharmaceutically acceptable carriers for rectal administration are preferably suppositories that may contain, in addition to the compounds of Formula I, excipients such as cocoa butter or a suppository wax.
The pharmaceutically acceptable carrier and compounds of this invention are formulated into unit dosage forms for administration to a patient. The dosage levels of active ingredient (i.e. compounds of this invention) in the unit dosage may be varied so as to obtain an amount of active ingredient effective to achieve lesion-eliminating activity in accordance with the desired method of administration (i.e., oral or rectal). The selected dosage level therefore depends upon the nature of the active compound administered, the route of administration, the desired duration of treatment, and other factors. If desired, the unit dosage may be such that the daily requirement for active compound is in one dose, or divided among multiple doses for administration, e.g., two to four times per day.
The pharmaceutical compositions of this invention are preferably packaged in a container (e.g. a box or bottle, or both) with suitable printed material (e.g. a package insert) containing indications, directions for use, etc.
For administration to humans in the curative or prophylactic treatment of the disorders identified above, oral dosages of a compound of Formula I will generally be in the range of from 0.01-1000 mg daily for an average adult patient, preferably from 0.1-500 mg of active compound more preferably, in a suitable pharmaceutically acceptable vehicle or carrier, for administration in single or multiple doses, once or several times per day. In practice, the physician will determine the actual dosing regimen that will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are believed to be exemplary of the average case, but there may be individual instances in which higher or lower dosage ranges may be merited, and such are within the scope of this invention.
A preferred group of compounds useful in the practice of this invention are those of formula I wherein R1 is selected from the group consisting of cyano, acyl, or lower alkyl optionally substituted with hydroxy; R2 is selected from the group consisting of hydrogen, acyl, lower alkenyl, or lower alkyl optionally substituted with lower alkoxy or hydroxy; R3 is methyl substituted with aryl or a heterocyclic group, wherein aryl is optionally substituted with one or more substituent selected from the group consisting of halogen, lower alkylenedioxy, protected carboxy and carboxy; or R1 and R2 together with the carbon atoms to which they are attached represent a 4- to 7-membered carbocyclic ring optionally substituted with oxo; and R4 is selected from the group consisting of acyl, cyano, or a heterocyclic group.
A more preferred group of compounds useful in the practice of this invention are those of formula I wherein R1 is selected from the group consisting of lower alkyl, or lower alkanoyl optionally substituted with hydroxy, lower alkoxy, or aryl; R2 is selected from the group consisting of hydrogen, lower alkenyl, or lower alkyl optionally substituted with lower alkoxy; and R3 is benzyl optionally substituted with one or more substituent(s) selected from the group consisting of halogen and lower alkylenedioxy.
A particularly preferred group of compounds useful in the practice of this invention are those of formula I wherein R4 is xe2x80x94C(O)NR5R6 wherein R5 is selected from the group consisting of hydrogen or lower alkyl, and R6 is selected from the group consisting of hydrogen, hydroxy, lower alkoxy, arylsulfonyl, a heterocyclic group, or lower alkyl optionally substituted with lower cycloalkyl or a heterocyclic group; or R5 and R6, together with the nitrogen atom to which they are attached, may represent a heterocyclic group.
An especially preferred group of compounds useful in the practice of this invention are those of formula I wherein R1 is selected from the group consisting of lower alkanoyl optionally substituted with alkoxy; R2 is lower alkyl; and R4 is carbamoyl.
Compounds of formula (I) may contain one of more asymmetric centers and thus can exist as enantiomers or diastereoisomers. Furthermore, certain compounds of formula (I) that contain alkenyl groups may exist as cis- or trans-isomers. In each instance, the methods of this invention can be practices with mixtures or separate individual isomers.
Compounds of formula (I) may also exist in tautomeric forms and the methods of this invention can be practiced with mixtures and separate individual tautomers. Solvates of compounds of formula (I) can also be used in the methods of this invention.
Compounds of Formula I may be prepared by any suitable method known in the art or by the following processes disclosed in WO96/32379, which is incorporated herein by reference. 
wherein
R1 to R6 are each as defined above,
Ra1 is lower alkanoyl optionally substituted with protected carboxy or carboxy,
Rb1 is lower alkyl optionally substituted with protected carboxy or carboxy,
Rc1 is lower alkenoyl, aroyl, or lower alkanoyl optionally substituted with protected carboxy, carboxy or aryl,
Rd1 is chloroacetyl,
Re1 is 
Rf1 is lower alkanoyl substituted with lower alkoxy,
Rg1 is lower alkanoyl substituted with hydroxy,
Rh1 is halogen,
R11 is lower alkyl optionally substituted with protected carboxy or carboxy,
Rj1 is lower alkanoyl,
Rk1 is hydroxyimino(lower)alkyl,
Ra2 is lower alkyl substituted with protected carboxy,
Rb2 is lower alkyl substituted with carboxy,
Rc2 is 1-hydroxy(lower)alkyl,
Rd2 is lower alkanoyl,
Ra3 is lower alkenyl or lower alkyl, both of which are optionally substituted with oxo and both of which are substituted with aryl which is substituted with protected carboxy,
Rb3 is lower alkenyl or lower alkyl, both of which are optionally substituted with oxo and both of which are substituted with aryl which is substituted with carboxy,
Rc3 is lower alkenyl or lower alkyl, both of which are optionally substituted with oxo and both of which are substituted with aryl which is substituted with 
Rd3 is lower alkenyl or lower alkyl, both of which are optionally substituted with oxo and both of which are substituted with aryl which is substituted with nitro,
Re3 is lower alkenyl or lower alkyl, both of which are optionally substituted with oxo and both of which are substituted with aryl which is substituted with amino,
Rf3 is lower alkenyl or lower alkyl, both of which are optionally substituted with oxo and both of which are substituted with aryl which is substituted with amino,
Rg3 is lower alkenyl or lower alkyl, both of which are optionally substituted with oxo and both of which are substituted with aryl which is substituted with amino substituted with acyl, Ra4 is protected carboxy or lower alkyl substituted with protected carboxy,
Rb4 is carboxy or lower alkyl substituted with carboxy,
Rc4 is 
xe2x80x83or lower alkyl substituted with 
R7 is hydrogen, protected carboxy, or 
R8 is acyl,
R9 is lower alkyl,
X1 is leaving group,
X2 and X3 are each as the same as X1, and
n is 1, 2, 3 or 4.
In the above and subsequent description of the present specification, suitable examples of the various definitions to be included within the scope of the invention are explained in detail in the following.
The term xe2x80x9clowerxe2x80x9d is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.
Suitable xe2x80x9clower alkylxe2x80x9d and lower alkyl moiety in the terms xe2x80x9clower alkoxyxe2x80x9d and xe2x80x9chydroxyimino(lower)alkylxe2x80x9d, may be a straight or branched C1-C6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or the like, in which preferable one is C1-C4 lower alkyl such as methyl, ethyl, propyl, butyl, isobutyl or tert-butyl.
Suitable xe2x80x9clower alkenylxe2x80x9d may be a straight or branched C2-C6 alkenyl such as ethenyl, propenyl (i.e. allyl or 1-propenyl), butenyl, isobutenyl, or the like.
Suitable xe2x80x9clower cycloalkylxe2x80x9d may include one having 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, or the like.
Suitable xe2x80x9carylxe2x80x9d and aryl moiety in the term of xe2x80x9carylsulfonylxe2x80x9d, xe2x80x9caroylxe2x80x9d and xe2x80x9car(lower)alkanoylxe2x80x9d may include phenyl, naphthyl, tolyl, mesityl, xylyl, or the like.
Suitable xe2x80x9chalogenxe2x80x9d may be fluoro, chloro, bromo or iodo.
Suitable xe2x80x9clower alkylenedioxyxe2x80x9d may include methylenedioxy, ethylenedioxy, or the like.
Suitable xe2x80x9cprotected carboxyxe2x80x9d may be a pharmaceutically acceptable and a common protected carboxy, such as an esterified carboxy, or the like, and concrete examples of the ester moiety in said esterified carboxy may be lower alkyl optionally substituted with aryl (e.g. methyl, ethyl, propyl, tert-butyl, benzyl, and so on).
Suitable xe2x80x9cheterocyclic groupxe2x80x9d may be one containing at least one hetero atom selected from nitrogen, sulfur and oxygen atom, and may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group such as
(1) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.], tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.;
(2) saturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.];
(3) unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g. tetrazolo[1,5-b]pyridazinyl, etc.], etc.;
(4) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.;
(5) unsaturated, 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms, for example, thienyl, etc.;
(6) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.], etc.;
(7) saturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.];
(8) unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl, etc.];
(9) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.], etc.
(10) saturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl, etc.];
(11) unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.];
(12) unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms or 1 to 2 oxygen atoms [e.g., benzothiophen, benzofuran, etc.]; or the like.
xe2x80x9cHeterocyclic groupxe2x80x9d defined above may be substituted with suitable substituent(s) such as lower alkyl, hydroxy, halogen, a heterocyclic group, or the like (e.g., 3-hydroxypyrrolidine, 4-methylpiperadine, 4-hydroxypiperidine, 1-methylimidazole, 4-(pyrimidin-2-yl)piperazin, and so on).
Suitable xe2x80x9cacylxe2x80x9d may be aliphatic acyl, aromatic acyl or aliphatic acyl optionally substituted aryl, which are derived from carboxylic acid or carbamic acid.
The aliphatic acyl may include
(1) lower alkanoyl optionally substituted with one or more suitable substituent(s) such as hydroxy, lower alkoxy, carboxy, protected carboxy, halogen, lower alkylthio, heterocyclicthio, oxo, cyclo(lower)alkyl or a heterocyclic group (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, 3,3-dimethylbutanoyl, 3-hydroxy-3-methylbutanoyl, 3-oxo-butanoyl, 3-methoxycarbonylpropanoyl, 3-carboxypropanoyl, 4-methoxycarbonylbutanoyl, 4-carboxybutanoyl, methylthioacetyl, (1-methylimidazol-2-yl)thioacetyl, hydroxyacetyl, methoxyacetyl, ethoxyacetyl, 3-methoxybutanoyl, chloroacetyl, morpholinoacetyl, piperidinylacetyl, 4-methylpiperidin-1-ylacetyl, 4-hydroxypiperidinyl, pyrolidinylacetyl, 4-(pyrimidin-2-yl)piperidinylacetyl, 3-hydroxypyrrolidinylacetyl, oxolan-4-ylacetyl, and so on);
(2) cyclo(lower)alkanecarbonyl (e.g. cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, and so on);
(3) lower alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, 3-methylbutanoyl, and so on);
(4) 
xe2x80x83(wherein R5 is hydrogen or lower alkyl, and R6 is hydrogen, hydroxy, lower alkoxy, arylsulfonyl, a heterocyclic group, lower alkyl optionally substituted with lower cycloalkyl or a heterocyclic group, or the like, in addition to their significances above, R5 and R6, together with the nitrogen atom to which they are attached, may represent a heterocyclic group), such as carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl, N-phenylsulfonylcarbamoyl, N-methoxycarbamoyl, N-(tetrazol-5-yl)carbamoyl, 1-pyrolidinylcarbonyl, piperidinocarbonyl, 4-methyl-1-piperazinylcarbonyl, 4-cyclohexyl-1-piperazinylcarbonyl, morpholinocarbonyl, 4-thiomorpholinylcarbonyl, or the like.
The aromatic acyl may include aroyl optionally substituted with one or more suitable substituent(s) such as nitro (e.g. benzoyl, naphthoyl, nitrobenzoyl, and so on), or the like.
The aliphatic acyl substituted with aryl may include ar(lower)alkanoyl which may have one or more suitable substituent(s) such as lower alkoxy (e.g. phenylacetyl, 4-methoxyphenylacetyl, and so on) or the like.
Suitable xe2x80x9carylsulfonylxe2x80x9d may include phenylsulfonyl, tosyl, methoxyphenylsulfonyl, or the like.
Suitable xe2x80x9cleaving groupxe2x80x9d may include hydroxy, halogen, acyloxy, in which the halogen and the acyl moiety may be those as exemplified above, or the like.
The starting compound (II) is prepared in similar manners to those of the below-mentioned Preparations.
Suitable salts of the compounds (I), (I-1) to (I-36) and (II) to (VII) may include pharmaceutically acceptable salts such as basic salts, for example, alkali metal salt (e.g. sodium salt, potassium salt, etc.), alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), ammonium salt, amine salt (e.g. triethylamine salt, N-benzyl-N-methylamine salt, etc.) and other conventional organic salts, or acid addition salts, for example, hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, or the like.
The processes for preparing the object compound (I) are explained in detail in the following.
The compound (I) or its salt can be prepared by reacting the compound (II) or its salt with the compound (III) or its salt.
This reaction is usually carried out in the presence of an inorganic or an organic base.
Suitable inorganic base may include an alkali metal [e.g., sodium, potassium, etc.], an alkali metal hydroxide [e.g., sodium hydroxide, potassium hydroxide, etc.], alkali metal hydrogen carbonate [e.g., sodium hydrogen carbonate, potassium hydrogen carbonate, etc.], alkali metal carbonate [e.g., sodium carbonate, etc.], alkali earth metal carbonate [calcium carbonate, etc.], or the like.
Suitable organic base may include tri(lower)alkylamine [e.g. triethylamine, N,N-diisopropylethylamine, etc.], alkyl lithium [e.g. methyl lithium, butyl lithium, etc.], lithium diisopropylamide, lithium hexamethyldisirazido, alkali metal hydride [e.g., sodium hydride, potassium hydride, etc.] or the like.
The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g., methanol, ethanol, isopropyl alcohol, etc.], tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
The object compound (I-2) or its salt can be prepared by subjecting a compound (I-1) to deesterification.
The reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like.
The hydrolysis is preferably carried out in the presence of a base, an acid, or the combination of Lewis acids and Lewis bases.
Suitable base may include an inorganic base and an organic base.
Suitable inorganic base may be the same as those exemplified in Process 1.
Suitable organic base may include tri(lower)alkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, or the like.
Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.], an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, etc.].
The hydrolysis is also carried out in the presence of the combination of Lewis acids and Lewis bases.
Suitable Lewis acid may include metal halide [e.g., aluminum chloride, aluminum bromide, titanium(IV) chloride, tin(IV) chloride, etc.], metal alkoxide [e.g., titanium(IV) isopropoxide, etc.] or the like.
Suitable Lewis base may include lower alkyl thiol [e.g., ethanethiol, ethanedithiol, etc.], di(lower)alkyl sulfide [dimethylsulfide, etc.], or the like.
The reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], xylene, diethylene glycol monomethyl ether, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction. A liquid base or acid can be also used as the solvent.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
The reduction can be applied preferably for elimination of the ester moiety such as 4-nitrobenzyl, 2-iodoethyl, 2,2,2-trichloroethyl, or the like. The reduction method applicable for the elimination reaction may include chemical reduction and catalytic reduction.
Suitable reducing agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid exemplified above.
Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalyst [e.g. platinum on carbon, platinum oxide, etc.], palladium catalyst [e.g. palladium black, palladium oxide, palladium on carbon, etc.] or any other catalyst ordinary employed in the field of organic synthetic chemistry. The catalytic reduction may be carried out in the presence of hydrogen or hydrogen doner such as formic acid, ammonium formate, cyclohexene, or the like.
The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, an alcohol [e.g. methanol, ethanol, propanol, etc.], N,N-dimethylformamide, or a mixture thereof. Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent. Further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc., or a mixture thereof.
The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
The compound (I-3) or its salt can be prepared by reacting the compound (I-2) or its reactive derivative at the carboxy group,.or its salt, with the compound (IV) or its reactive derivative at the amino group, or its salt, according to any well known procedure.
Suitable reactive derivative at the amino group of the compound (IV) may include Schiff""s base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (IV) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (IV) with a silylating reagent such as trimethylsilyl chloride, N,O-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide, or the like.
Suitable reactive derivative of the compound (I-2) may include an acid chloride, acid azide, an acid anhydride, an activated amide, an activated ester, or the like.
The suitable acid anhydride may include a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfuric acid, thiosulfuric acid, alkanesulfonic acid (e.g., methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkanoic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid, etc.), aromatic carboxylic acid (e.g., benzoic acid, chlorobenzoic acid, fluorobenzoic acid, nitrobenzoic acid, etc.),or the like.
Suitable activated amide may be imidazoylamide, 4-substituted imidazoylamide, dimethylpyrazolylamide, triazolylamide tetrazolylamide, or the like.
Suitable activated ester may be dimethyliminomethyl [(CH3)2Nxe2x95x90CHxe2x80x94] ester, vinyl ester, propargyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenol ester, pentafluorophenyl ester, methanesulfonylphenyl ester, phenyl thioester, p-nitrophenyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, 8-quinolyl thioester, an ester with a N-hydroxy compound (e.g., N,N-dimethylhydroxylamine, 1-hydroxy-2H-pyridone, N-hydroxysuccinimido, N-hydroxybenzotriazole, N-hydroxyphthalimide, etc.), or the like.
These reactive derivatives can optionally be selected from them according to the kind of compound (I-2) to be used.
When the compound (I-2) is used in free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of condensing agent.
Suitable condensing agent may include a carbodiimide (e.g., N,N-dicyclohexylcarbodiimide, N-cyclohexyl-Nxe2x80x2-(4-diethylaminocyclohexyl)carbodiimide, N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide or its hydrochloride, etc.) diphenylphosphinic azido, diphenylphosphinic chloride, diethylphosphoryl cyanide., bis(2-oxo-3-oxazolidinyl)-phosphinic chloride, N,Nxe2x80x2-carbonyldiimidazole, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, cyanuric chloride, or the like.
The reaction may be also carried out in the presence of organic or inorganic base such as alkali metal carbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine, or the like.
The reaction is usually carried out in a conventional solvent such as water, acetone, alcohol [e.g., methanol, ethanol, isopropyl alcohol, etc.], tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
The compound (I-5) or its salt can be prepared by subjecting the compound (I-4) or its salt to deesterification.
This deesterification can be carried out in a similar manner to that of the Process 2, and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process 2.
The compound (I-6) or its salt can be prepared by reacting the compound (I-5) or its reactive derivative at the carboxy group, or its salt, with the compound (IV) or its reactive derivative at the amino group, or its salt.
This reaction can be carried out in a similar manner to that of the Process 3, and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process 3.
The compound (I-8) or its salt can be prepared by reacting a compound (I-7) or its salt with a reducing agent.
Suitable reducing agent may be diborane, sodium borohydride, lithium aluminum hydride or the like.
The reaction is usually carried out in a conventional solvent such as diethyl ether, tetrahydrofuran or any other organic solvent which dose not adversely influence the reaction.
The reaction temperature is not critical, and the reaction can be carried out under cooling to heating.
The compound (I-10) or its salt can be prepared by reacting the compound (I-9) or its salt with an acylating agent (V).
Suitable acylating agent (V) may be a conventional one used in the Friedel-Crafts acylation reaction such as an acid halide [e.g. acid chloride, acid bromide, etc.], an acid anhydride or the like.
This reaction is preferably carried out in the presence of a Lewis acid such as aluminum halide [e.g. aluminum chloride, aluminum bromide, etc.], titanium halide [e.g. titanium tetrachloride, etc.], zinc halide (e.g. zinc chloride), boron trifluoride or the like.
The reaction is usually carried out in a conventional solvent such as carbon disulfide, dichloroethane, tetrachloromethane, benzene or any otherorganic solvent which does not adversely influence the reaction.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
The compound (I-12) or its salt can be prepared by subjecting the compound (I-11) or its salt to dehydration at the carbamoyl group.
Dehydration is carried out in the conventional manner, which is capable dehydrating a carbamoyl group to cyano group, and suitable dehydrating agent may be phosphorus compound (e.g. phosphorous pentoxide, phosphorus pentachloride, phosphorous oxychloride, pyrocatechyl phosphorus trichloride, and so on); thionyl chloride; or a combination of triaryl phosphine (e.g. triphenyl phosphine, and so on) and chloroform or carbon tetrachloride.
The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, carbon tetrachloride, N,N-dimethylformamide or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
The object compound (I-13) or its salt can be prepared by reacting a compound (I-12) or its salt with an azide compound.
Suitable azide compound may be alkali metal azide [e.g. sodium azide, potassium azide, etc.], alkaline earth metal azide [e.g. calcium azide, etc.], aluminum azide, hydrogen azide, trimethyltin azide, or the like.
The reaction is preferably carried out in the presence of ammonium halide [e.g. ammonium chloride, ammonium bromide, etc.], lower alkylammonium halide [e.g. trimethylammonium chloride, triethylammonium chloride, etc.] or the like.
The reaction is usually carried out in a conventional solvent such as tetrahydrofuran, dioxane, N,N-dimethylformamide or any other organic solvent which does not adversely influence the reaction.
The reaction temperature is not critical, and the reaction can be carried out under warming to heating.
The compound (I-15) or its salt can be prepared by subjecting the compound (I-14) or its salt to deesterification.
This deesterification can be carried out in a similar manner to that of the Process 2, and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process 2.
The compound (I-16) or its salt can be prepared by subjecting the acid chloride or acid anhydride derived from the compound (I-15) or its salt to intramolecular acylation reaction.
This intramolecular acylation reaction can be carried out in a similar manner to that of the Process 7, and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process 7.
The compound (I-18) or its salt can be prepared by reacting the compound (I-17) or its salt with compound (IV).
This reaction is preferably carried out in the presence of organic or inorganic base exemplified in Process 1, and/or alkali metal iodide (e.g. sodium iodide, potassium iodide, etc.).
The reaction is usually carried out in a solvent such as water, tetrahydrofuran, dioxane, N,N-dimethylformamide or any other solvent which does not adversely influence the reaction.
The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature of under warming to heating.
The compound (I-19) or its salt can be prepared by reacting a compound (I-9) or its salt with a formylating agent.
Suitable formylating agent may be N,N-dimethylformamide; (CH3)2N+xe2x95x90CHCl.Cl2PO2xe2x88x92 (so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with phosphorus oxychloride, phosgene, etc.); or the like.
When a formylating agent is N,N-dimethylformamide, the reaction is preferably carried out in the presence of a base such as lower alkyl alkali metal [e.g. n-butyl lithium, ethyl magnesium bromide, etc.], or the like.
The reaction is usually carried out in a solvent such as dioxane, tetrahydrofuran, N,N-dimethylformamide, methylene chloride, chloroform, or any other organic solvent which does not adversely influence the reaction.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
The compound (I-20) or its salt can be prepared by subjecting the compound (I-19) or its salt to oxidation reaction.
Oxidation is carried out in a conventional manner, which is capable of oxidizing formyl group to carboxy group, and suitable oxidizing reagent may be oxygen acid such as periodate (e.g. sodium periodate, potassium periodate, etc.), peroxy acid such as peroxybenzoic acid (e.g., peroxybenzoic acid, m-chloroperoxybenzoic acid, etc.), potassium permanganate, cromic acid, sodium hypochlorite, or the like.
The reaction is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, dichloromethane, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, or any other organic solvent which does not adversely affect the reaction.
Among these solvents, hydrophilic solvents may be used in a mixture with water.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
The compound (I-22) or its salt can be prepared by subjecting the compound (I-21) or its salt to a rearrangement reaction.
The rearrangement reaction, which is capable of converting the carboxy group into amino group optionally substituted with protected carboxy or acyl (e.g. Carbamoyl substituted with lower alkyl, etc.), may be the condition such as Curtius Rearrangement, Hoffmann reaction, Schmidt reaction, or the modification thereof.
For example, the Curtius rearrangement consists of the formation of acid azide, the decomposition of acid azide to isocyanate and nitrogen, and the reaction of isocyanate with water, alcohol or amine to afford amine, urethane or urea, respectively.
Acid azide can be prepared by treating corresponding acid hydrazide with nitrous acid, treating corresponding acid chloride with alkali metal azide, treating carboxylic acid with diphenylphosphoryl azide, or the like.
Acid azide can be rearranged in inert solvent (e.g., toluene, dichloromethane, etc.), from which the isocyanate can be isolated, or in the presence of reagents like alcohol or amine which will react with the intermediate isocyanate to form urethan or urea. Amine or its salt can be obtained by hydrolysis of isocyanate, urethan, or urea.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
The compound (I-24) or its salt can be prepared by reacting the compound (I-23) or its reactive derivative at the amino group, or its salt, with the compound (VI) or its salt, or the compound (VII) or its salt.
When free acid is used as the compound (VI), the reaction is preferably carried out in the presence of condensing agent exemplified in Process 3.
The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g., methanol, ethanol, isopropyl alcohol, etc.], tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
The compound (I-26) or its salt can be prepared by subjecting a compound (I-25) or its salt to reduction.
The present reduction is carried out by chemical reduction, catalytic reduction, or the like.
Suitable reducing agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.].
Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalyst [e.g. platinum, platinum black, platinum oxide, etc.], palladium catalyst [e.g. palladium black, palladium oxide, palladium on carbon, etc.], nickel catalyst [e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalyst [e.g. reduced cobalt, Raney cobalt, etc.], iron catalyst [e.g. reduced iron, Raney iron, etc.], copper catalyst [e.g. reduced copper, Raney copper, Ullman copper, etc.] or the like.
The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, an alcohol [e.g. methanol, ethanol, propanol, etc.], N,N-dimethylformamide, or a mixture thereof. Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent. Further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent and other conventional solvent such as diethyl ether, methylene chloride, dioxane, tetrahydrofuran, etc., or a mixture thereof.
The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
The compound (I-28) or its salt can be prepared by subjecting a compound (I-27) or its salt to cleavage of ether bond.
The cleavage of ether bond is carried out in the presence of an acid including Lewis acid [e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, boron tribromide, boron trichloride, etc.], tri(lower)alkylsilyliodide [e.g. trimethylsilyliodide, etc.], or any other method ordinary employed in the field of organic synthesis.
The reaction is usually carried out in a solvent such as water, acetic acid, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
The compound (I-30) or its salt can be prepared by subjecting the compound (I-29) or its salt to oxidation.
This oxidation can be performed according to the general procedures ordinarily employed in the field of organic chemistry, which is capable of oxidizing a secondary alcohol to ketone, and suitable oxidizing agent is, for example, derivatives of hexavalent chromium(CrVI) (e.g. chromium trioxide, sodium dichromate, chromium trioxide-dipyridine complex, etc.) or heptavalent manganese(MnVII) (e.g. potassium permanganate, manganese dioxide, etc.).
The reaction is usually carried out in a conventional solvent such as water, tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide, acetone, or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
The compound (I-31) or its salt can be prepared by subjecting the compound (I-9) or its salt to halogenation.
This halogenation is usually carried out by using a conventional halogenating agent such as halogen (e.g., chlorine, bromine, etc.), phosphorus trihalide (e.g., phosphorus tribromide, phosphorus ichloride, etc.), phosphorus pentahalide (e.g., phosphorous pentachloride, phosphorus pentabromide, etc.), phosphorus oxychloride (e.g., phosphoryl trichloride, phosphoryl monochloride, etc.), thionyl halide (e.g., thionyl chloride, thionyl bromide, etc.), oxalyl halide (e.g., oxalyl chloride, oxalyl bromide, etc.), sulfuryl halide (e.g. sulfuryl chloride, etc.), pyridinium hydrobromide perbromide, or the like.
This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), benzene, dioxane, N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene dichloride, chloroform, diethyl ether or any other solvent which dose not adversely affect the reaction.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
The compound (I-32) or its salt can be prepared by reacting a compound (I-9) or its salt with a nitrating agent.
Suitable nitrating agent may be nitric acid, fuming nitric acid, potassium nitrate, nitronium tetrafluoroborate or the like.
The reaction is usually carried out in an acid or an acid anhydride such as sulfuric acid, acetic acid, acetic anhydride or the like.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
The compound (I-33) or its salt can be prepared by subjecting the compound (I-7) or its salt to reduction.
This reduction can be performed according to the general procedures ordinarily employed in the field of organic chemistry, which is capable of reducing a ketone to a secondary alcohol, and suitable reducing agent is, for example, metal hydride such as aluminum hydrides (e.g. lithium aluminum hydride, lithium di(lower)alkylaluminum hydride, Red-A1(copyright), etc.), boron hydrides (e.g. sodium borohydride, sodium borocyanohydride, etc.), or the like.
The reaction is usually carried out in a conventional solvent such as water, tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide, acetone, or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
The compound (I-35) or its salt can be prepared by reacting a compound (I-34) or its salt with hydroxylamine or its salt.
The reaction is usually carried out in a conventional solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, dioxane or any other organic solvent which does not adversely influence the reaction. These conventional solvents may also be used in a mixture with water.
The reaction is preferably carried out in the presence of an inorganic or organic base exemplified in Process 1.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
The compound (I-37) or its salt can be prepared by reacting the compound (I-36) or its reactive derivative at the amino group, or its salt with the compound (VI) or compound (VII).
This reaction can be carried out in a similar manner to that of Process 16 and therefore the regents to be used and the reaction conditions (e.g. reaction temperature, etc.) can be referred to those of the Process 16.
The compounds (I) and pharmaceutically acceptable salts thereof of the present invention possess inhibitory activity of cGMP-PDE (especially PDE-V), relaxant activity of smooth muscle, bronchodilator activity, vasodilative activity, inhibitory activity of smooth muscle cells proliferation, inhibitory activity of allergy, and so on.
The compounds (I) and pharmaceutically acceptable salts thereof, therefore, have utility in the treatment and intramuscular, or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable, carriers for ointment, cream, plaster, tablets, pellets, capsules, suppositories, solutions (saline, for example), emulsion, suspensions (olive oil, for example), and any other form suitable for use. The carriers which can be used are water, wax, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, paraffin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The active compound is included in the pharmaceutical composition in an effective amount sufficient to produce the desired effect upon the process or condition of the diseases.
Mammals which may be treated by the present invention include livestock mammals such as cows, horses, etc., domestic animals such as dogs, cats, rats, etc. and humans, preferably humans.
For applying this composition to a human, it is preferable to apply it by external (topical), oral, parenteral, enteral, intravenous, or intramuscular administration.
While the dosage of therapeutically effective amount of the macrolide compounds varies from and also depends upon the age and condition of each individual patient to be treated, in case of the systemic administration; a daily dose of about 0.01-1000 mg, preferably 0.1-500 mg and more preferably 0.5-100 mg of the active ingredient is generally given for treating the diseases, and an average single dose of about 0.2-0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg and 500 mg is generally administered. Daily doses for chronic administration in humans will be in the range of about 0.3